DE3520896A1 - Novel pterin derivatives and medicaments containing them - Google Patents

Abstract

Novel pterin derivatives have an acyl radical substituted by hydroxyl, halogen and/or amino groups and which can in turn optionally contain hetero atoms. The novel compounds can be contained in medicaments, in particular with neuroregulatory action.

Description

New pterin derivatives and drugs containing them

Description: The invention relates to new pterin derivatives which at least one substituted by hydroxyl, halogen and / or amino groups th acyl radical of the general formula RC- contain, where R is an optionally Cl-C8 radical additionally containing sulfur, nitrogen and / or oxygen atoms is. The hydroxyl, halogen and / or are preferably in the new pteridine derivatives Amino groups in the acyl residue arranged in a-position. The acyl residue is particularly the acid residue of a natural amino acid in proteins.

Another preferred class of pteridine derivatives of the aforementioned type, in particular the 5,6,7,8-tetrahydropterin derivatives, are those in which the acyl radical is directly or via a spicer on the 2-amino group, on the N-5 -Atom and / or in 6-position or as with biopterin or tetrahydrobiopterin (BH4) are arranged in the side chain in 6-position. It is precisely these tetrahydropterin conjugates with amino acids, which can be explained in exemplary form by the following general formulas (I-IV), are of particular interest: R1 = H; CH3; CH20H; CH2SH; CH2SCH3; CH (CH3) 2i CH2 CH (CH3) 2 CH (CH3) C2H5; CH2CH2SCH3; CH (OH) CH3; CH2CH2CONH2; CH2COOH R2 = H; ALKYL; HYDROXYALKYL; ARYL The present invention includes, in addition to the aforementioned tetrahydrobiopterin derivatives, also compounds of the following general formulas (V) and (VI), in which R can again be the residue derived from a natural amino acid of the proteins, in particular can have the aforementioned meaning: R3 = H; ALKYL; HYDROXYALKYL R4 = H; ALKYL; HYDROXYALKYL ARYL; CYCLOALKYL ARYL R5 = H; OH; OALKYL If the acyl radicals of the compounds according to the invention contain the radical of an aminodicarboxylic acid, such as glutamic acid and aspartic acid, these acyl radicals can be linked to the pterin derivative via the α-carboxyl group (VII) or the ω-carboxyl group (VIII) be: The substituent R 'can have the meaning already mentioned at the beginning.

As can be seen from the explanations above, it is in the acyl compounds according to the invention to derivatives, which in particular are pterine base bodies are based on, in addition to the 2-amino group in the 4-, 6- and / or 7-position have a hydroxyl group or, in the tautomeric form, a keto group. To the Basic bodies also include the corresponding 5,6,7,8-tetrahydro compounds, namely but biopterin or 5,6,7,8-tetrahydrobiopterin derivatives. In addition to the 5,6,7,8-tetrahydropterin The present invention also includes such acyl derivatives, in particular with a natural amino acid acyl residue, which is the basic structure of the 6-methyl-, 6-hydroxymethyl-, 6,7-dimethyl- or 6,6-dimethyl tetrahydropterin is the basis.

The compounds according to the invention are regularly included in the new compounds Acyl group contained in the pterine body via an ester and / or amide bridge tied together.

Pterines, as derivatives of pteridine, are widespread natural substances of major importance. In addition to the compounds isolated from animal bodies at an early stage such as leucopterin or xanthopterin and eye pigments such as drosopterin A whole series of growth factors separate from the pterins. Tetrahydropterins, namely the 5,6,1,8-tetrahydropterins, are essential enzymatic importance. Specifically, the 5,6,7,8-tetrahydrobiopterin falls as a cofactor various aromatic amino acid hydroxylases play an important regulatory role in the synthesis of biogenic amines that act as neurotransmitters.

It has been observed that the physiological activity of the known Pterine derivatives are sometimes unsatisfactory. In particular, it has been observed that the Cofactor activity of tetrahydrobiopterin (BH4) when administered orally or intravenously only has a very bad effect. Polarities may play a role here overcoming the blood-brain barrier plays a role.

Surprisingly, it has now been found that the invention Pterin derivatives, especially the tetrahydropterin derivatives, have a different polarity and possibly due to their different reactivity with the help of an active one Transport mechanism the prerequisites for an easier smuggling e.g. in the brain, and generally higher activity.

Accordingly, the present invention also relates to medicaments with a content of the compounds according to the invention. Are preferred those drugs containing the acyl derivatives derived from natural amino acids des 5,6,7,8-tetrahydrobiopterin.

The compounds according to the invention are, for example, by customary Acylation process easy to produce.

The following examples serve to illustrate the invention.

N2 -Isobutyryl-6,7-dimethylpterin -6,7-dimethylpterin (15.0 g, 0.078 Mol) are syspendiert in 200 ml of dry pyridine and then in the course of 15 min 45 ml of isobutyric anhydride were added dropwise. The mixture is then refluxed for 4 hours heated, with complete dissolution occurring. After cooling, 40 ml of methanol are used to, stirred for 30 min and then concentrated in vacuo.

The residue is twice with 50 ml of toluene and then 100 ml of hexane coevaporated and then treated the residue with hexane and the resulting precipitate sucked off. 20.0 g (98%) of colorless crystals with a melting point of 262-264 ° C. (decomp.) Are obtained. The product can be recrystallized from chloroform / hexane 2 N -isobutyryl-5,6,7,8-tetrahydro-6,7-djmethylpterin -N2-Isobutyryl-6,7-dimethylpterin (6.0 g, 0.023 mol) are dissolved in 100 ml of methanol in the shaking duck with the addition of 5% platinum on activated carbon catalyst (0.18 g) hydrogenated. After taking up the theoretical amount of hydrogen, the vessel is filled with ice / table salt mixture cooled, then 10 ml of concentrated hydrochloric acid were added, with the deposited precipitate then dissolves again. All operations are carried out under nitrogen to avoid possible oxidation of the tetrahydropterin. The catalyst is filtered off and then instilled into cooled ether (200 ml) with stirring. Cool to OOC collects the precipitate and dries in vacuo, leaving 6.79 g (92%) colorless Product of m.p. 212-2150C (decomp.) Can be isolated. It is according to the elemental analysis around the monohydrochloride monohydrate salt of the empirical formula C12HlgN502 x HC1 x H 20.

N²-Isobutyryl-5,6,7,8-tetrahydro-6,7-dimethyl-5-succinylpterin-9 N²-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin monohydrochloride monohydrate (3.00 g, 9.4 Mmol) becomes a solution of succinic anhydride (3.0 g, 3Q Mmol) in 40 ml absolute Given pyridine and then the mixture for 2 hours at room temp. touched. 4 ml of methanol are then added, the mixture is stirred for a further 15 minutes and then concentrated in vacuo Dry up. The oily residue is treated with warm ether until solid Precipitation separates. The product is then treated with ice water, pH-1 with Adjusted acid, and then collected the material by suction. You wash with Water and dried in vacuo, 2.80 g (86%) of colorless crystals of mp. 176-1770C. The substance can be recrystallized from methanol water are and accrues as a monohydrate.

N- (4- (N²-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin-5-yl) -1,4-dioxobutyl) -glutamic acid dibenzyl ester-N²-isobutyryl-5,6,7, 8-tetrahydro-6,7-dimethyl-5-succinylpterin (1.1 g, 3.0 Mmol), glutamic acid dibenzyl ester monotosylate (1.49 g, 3.3 Mmol) and N-Hydroxy-5-norbornene-2,3-dicarboxamide (0.59 g, 3.3 Mmol) are dissolved in 30 ml of methylene chloride dissolved and then cooled to 0 ° C. One sets Triethylamine (0.33 g, 3.3 Mmol), stir for 15 min and then add dicyclohexylcarbodiimide (0.68 g, 3.3 Mmol) to the reaction solution, which is then 2 hours at OOC and then 21 hours. at room temp.

is stirred. The precipitate of dicyclohexylurea is filtered off, washed with methylene chloride and the filtrate concentrated to dryness in vacuo. Man dissolves the residue in 200 ml of ethyl acetate, washed successively with 4 percent. watery Sodium bicarbonate (2 x 25 0.2 M aqueous acetic acid (2x50 ml), 4% aqueous Sodium bicarbonate (2x25 ml) and water (2x25 ml). The organic phase w rd over Dried sodium sulfate, then filtered and concentrated. The residue is through Purified chromatography on a silica gel column in the system chloroform / methanol (9/1), 1,623 g (80%) of a colorless solid being obtained from the main fraction after concentration Foam is obtained from which crystals are formed by recrystallization from ethyl acetate / ether of m.p. 184-185 ° C.

N- (4- (N2-isobutyryl -5,6, 7,8-tetrahydro-6,7-dimethylpterin-5-yl) -1,4-dioxobutyl) -glutamic acid -N- (4- (N2-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin-5-yl) -1,4-dioxobutyl) -glutamic acid dibenzyl ester (1.11 g, 2.24 Mmol) is dissolved in 50 ml of methanol over a palladium catalyst (5% Pd Activated charcoal, 100 mg) hydrogenolytically debenzylated. It is shaken over hydrogen for 5 hours in the shaking duck at room temperature, then filtered off the catalyst and the filtrate is concentrated to dryness. The residue is dissolved in 10 ml of methanol and this solution was slowly added dropwise with stirring into 100 ml of ether. The retired Precipitate is collected, washed with ether, dried and yields 0.77 g (95 , ú) colorless product, which after recrystallization from a little 0.1 M aqueous HC1 provides colorless crystals.

N- (4- (5,6,7,8-tetrahydro-6,7-dimethylpterin-5-yl) -1,4-dioxobutyl) -glutamic acid -N- (4- (N²-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin-5-yl) -1,4-dioxobutyl) -glutamic acid (0.7 g, 1.4 Mmol) is dissolved in 3 ml of methanol and then with 3 ml of conc. Ammonia solution offset. The mixture is stirred for 8 hours at room temperature, then evaporated to dryness and the residue is dissolved in 20 ml of methanol and then separates the product by adding acetone. Man sucks off, dries and receives 0.6 g (92%) of a colorless substance that consists of little 0.1 M hydrochloric acid can be recrystallized to give colorless crystals.

5- (2'-N -benzyloxy carbonylamine acetyl) -N2-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin-N²-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin -monohydrochloride monohydrate (1.00 g, 3.13 mmol) and N-benzyloxycarbonylglycine-N-hydroxysuccinimide esters (1.92 g, 6.27 mmol) are in 20 ml of pyridine initially for 2 hours at 600 "and then heated for a further hour 0 at 30 ° C under nitrogen. After the reaction has ended 4 ml of methanol are added, the mixture is stirred for 15 min and, after cooling to room temperature, concentrated in a vacuum to dryness. The residue is coevaporated 3 times with 25 ml of toluene each time. The residue is then taken up in 100 ml of chloroform and washed twice with 25 ml each time 4 percent Sodium bicarbonate solution and then twice more with water. The organic Phase is dried over sodium sulfate, concentrated, and for purification on a Chromatographed silica gel column with chloroform / methanol (9/1). The main faction is collected, concentrated, and the residue is recrystallized from ethyl acetate / ether, 1.14 g (80.0) of colorless crystals of m.p. 152-1540C 2 5- (2'-aminoacetyl) -N2-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin -5- (2'-N-Benzyloxycarbonylaminoacetyl) -N²-isobutyryl-5,6,7,8-tetrahydro-6,7-dimethylpterin (0.56 g, 1.23 mmol) are dissolved in 20 ml of methanol with a palladium / activated carbon catalyst (5%, 50 mg) in the shaker duck at room temp. hydrogenated. To The reaction has ended in 5 hours and the catalyst is filtered off. You narrow it down Filtrate to approx.

5 ml and slowly drip this concentrate into 100 ml absolute Ether. The precipitate which separates out is collected and washed with ether and dried in vacuo, 0.36 g (91 ° h) of the reaction product in the form of the Monohydrochloride salt is obtained.

The substance can be made from ethanol / O.l mol aq. HCl / ether recrystallized will.

5- (2'-aminoacetyl) -5,6,7,8-tetrahydro-6,7-dimethylpterin -5- (2'-aminoacetyl) -N2-isobutyryl-5,6,7,8-tetrahydro-6, 7-dimethylpterin (0.2 g, 0.62 mmol) is under nitrogen at room temp. in a mixture of 1 ml conc. Ammonia and 1 ml of methanol were stirred for 8 hours. One concentrates in a vacuum, takes the residue in 10 ml of methanol and separates the product by dropping in Acetone from with stirring. The precipitate is collected, washed with acetone and dried in vacuo, 0.144 g (92%) of the dihydrochloride salt being obtained. The dihydrochloride salt can be obtained from a mixture of ethanol / 0.1 M aq. HCl / ether recrystallized will.

Claims (6)

P a t e n t a n s p r ü c h e: 1. Pterine derivatives, d a d u r c h it is not noted that they have at least one, by hydroxy, halogen and / or Amino groups contain substituted acyl radical of the general formula RC-O, in which R is an optionally additionally containing sulfur, nitrogen and / or oxygen atoms C1-C8 residue. 2. Pterin derivatives according to claim 1, d a d u r c h g e -k e n n z e i c h n e t that the hydroxyl, halogen and / or amino group in the acyl radical is arranged in the α position. 3. Pterin derivatives according to claim 1 or 2, d a d u r c h g e it is not noted that the acyl residue is the acid residue of a natural amino acid is. 4. Pterin derivatives, in particular tetrahydropterin derivatives, according to a of the preceding claims, d a d u r c h g e n n n z e i c h n e t that the acyl radical directly or via a spicer on the 2-amino group, on the N-5 atom and / or in the 6-position or on a side chain of the pterin in the 6-position or Tetrahydropterins is arranged. 5. Medicines that are not indicated that the a connection according to one of the preceding claims, if necessary with pharmaceutically acceptable ingredients included. 6. Use of the compounds and drugs according to any of the preceding Claims as neuroregulators.